In this project we seek to advance the understanding of the physiology and pathophysiology of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. The role of stress-related hormones in normal and disease states is being examined, and clinical applications for these hormones are sought. The discovery of the structure of corticotropin releasing hormone (CRH) and the development of sensitive assays for measuring HPA- and HPG-related hormones and their receptors have led to rapid progress in this field. Major progress has been made in three areas: 1) Clinical applications of CRH: An ovine (o) CRH stimulation test has been developed that is useful in the differential diagnosis of adrenal insufficiency, Cushing's syndrome, and pseudo-Cushing's states (psychiatric hypercortisolism). The oCRH test and/or measurements of CSF CRH have increased our understanding of the pathophysiology of Cushing's syndrome, melancholic depression, childhood sexual abuse, atypical/seasonal depression, the chronic fatigue/fibromyalgia syndromes, diabetes mellitus, rheumatoid arthritis, and the postpartum blues/depression syndromes. 2) The regulation of the axis by neurotransmitters, neuropeptides, and glucocorticoids has been studied in vivo and/or in vitro. Third trimester pregnant women and athletes have a hyperfunctional pituitary- adrenal axis in the resting state. The hCRH gene 5' regulatory region has been cloned and sequenced and its regulation has been studied. It has 2 active promoters and responds positively to estrogens, providing a potential explanation for the sexual dimorphism of psychiatric diseases characterized by aberrations in CRH secretion. 3) Roles and actions of HPA and HPG axes hormones. Glucocorticoid resistance is an autosomal recessive or dominant disease associated with abnormalities of the glucocorticoid receptor. We have elucidated the molecular pathophysiology of this syndrome by defining mutations and/or deletion of the glucocorticoid receptor gene leading to abnormal or decreased receptors in the tissues of patients. The mineralocorticoid receptor and the subunits of the amiloride-sensitive sodium channel are studied in sporadic cases of pseudohypoaldosteronism or mineralocorticoid resistance. The interaction of the classic glucocorticoid receptor (GRalpha) and its nonligand binding natural homolog glucocorticoid receptor beta (GRbeta) with each other and with the heat-shock proteins and glucocorticoid-responsive elements (GREs) of the DNA are studied, as the well as the importance of GRbeta in human physiology and pathophysiology. We have elucidated the molecular pathophysiology of hereditary ACTH resistance, an autosomal recessive disorder characterized by isolated glucocorticoid deficiency, by defining abnormalities of the ACTH receptor gene. We have elucidated the molecular pathophysiology of testicular and ovarian resistance to luteinizing hormone (LH) by defining abnormalities of the LH receptor gene. We have localized the gene for Carney Complex, a multiple neoplasia/lentiginosis syndrome, on chromosome 2p16, and have characterized it as a protooncogene. We have defined the molecular defect in the excessive aromatase syndrome.